INTRODUCTION
Distal intestinal obstruction syndrome is a well-recognized complication of cystic fibrosis. Common symptoms include constipation, abdominal pain, anorexia, and early satiety. Less commonly distal intestinal obstruction syndrome can be associated with complete intestinal obstruction, intussusception, and volvulus (1). Although the prevalence of distal intestinal obstruction syndrome in patients with cystic fibrosis is commonly reported to be between 5 and 15%, more recent reports suggest a greater prevalence, ranging from 30 and 73% with the highest rates in older patients (2).
A variety of treatments has been proposed to treat this disorder, including oral N-acetylcysteine, mineral oil, or Gastrograffin® (sodium meglumine diatrizoate; Squibb Diagnostics, Evansville, IN) or enemas containing N-acetylcysteine or Gastrograffin® (3-7). More recently, intestinal lavage with a balanced electrolyte solution has been recommended (3-4,6). In rare cases, surgery is required (2,8,9). Although one study suggested that cisapride might lessen the recurrence risk of distal intestinal obstruction syndrome (10), no studies have examined the role of prokinetic agents in treating acute episodes.
We describe a young woman with cystic fibrosis and refractory distal intestinal obstruction syndrome whose symptoms did not respond to oral laxative therapy, repeated courses of intestinal lavage with a balanced electrolyte solution, or repeated Gastrograffin® enemas but who experienced a dramatic response to intravenous neostigmine.
CASE REPORT
A 21-year-old female with cystic fibrosis was admitted to the University of Virginia Children's Medical Center for treatment of an acute exacerbation of pulmonary disease. She also complained of worsening constipation, abdominal discomfort, and abdominal distension. During the week before her hospital admission she had been unable to tolerate her nightly tube feedings. She complained of abdominal bloating and nausea as well as repeated bouts of vomiting. The diagnosis of cystic fibrosis had been made at two years of age. Insulin-dependent diabetes had been present since 10 years of age. She had been hospitalized with increasing frequency over the previous two years for exacerbations of her lung disease. Her diabetes was poorly controlled and typically worsened during pulmonary exacerbations. She had experienced long-standing difficulties maintaining adequate nutrition, and a feeding gastrostomy had been placed 11 months before this admission through which she received nocturnal drip feedings of a high-calorie formula.
The patient had a several-year history of constipation, abdominal pain, abdominal bloating, feeding intolerance, and vomiting attributed to recurrent distal intestinal obstruction syndrome. Previous radiographic evaluation of her intestinal tract had included an upper GI series with small bowel follow-through and a barium enema. These contrast studies revealed no mucosal abnormalities or nodularity and no colonic strictures, longitudinal shortening, or haustral abnormalities suggestive of fibrosing colonopathy. In addition to numerous medications for her pulmonary disease, she routinely took four Ultrase® MT-20 capsules (Axcan Scandipharm Inc., Birmingham, AL) with each meal (80,000 U of lipase or approximately 1500 U/kg/meal), 1 tablet of Senokot® twice daily (Purdue Frederick, Stamford, CT), and 2 tbsp of Miralax® (Braintree Pharmaceuticals, Braintree, MA) three times daily. She also had been treated intermittently with intestinal lavage with a balanced electrolyte solution (Golytely®) through her gastrostomy tube as well as intermittent large-volume hyperosmolar enemas (Gastrograffin®). The results of these interventions were generally modest and temporary.
On physical examination, the patient was slender and undernourished. Her height was 157 cm and her weight was 49.1 kg. She appeared chronically ill. She was dyspneic at rest with mild nasal flaring. She was afebrile. Her heart rate was 100 beats/min, her respiratory rate was 28 breaths/min, and her blood pressure was 94/60 mm Hg. Her oxygen saturation was 77% in room air and it increased to 93% after 2 l/min of oxygen was administered via nasal cannulae. She had a barrel-shaped chest and there were crackles throughout all lung fields. She had prominent digital clubbing. Her abdomen was distended. She had a well-healed gastrostomy. Abdominal palpation revealed fullness and tenderness on the right side without organomegaly or ascites. Bowel sounds were normal.
An abdominal radiograph demonstrated a large amount of fecal material in the ascending, transverse, and descending colon. The patient was treated with intravenous and aerosolized antibiotics, bronchodilators, mucolytics, and aggressive chest physiotherapy and her pulmonary function returned to baseline over the next several days. She continued to experience abdominal distension, pain, and constipation. She did not tolerate overnight tube feedings; rather, she experienced worsening abdominal pain and bloating and repeated episodes of vomiting. Treatment with high doses of Senokot®, Milk of Magnesia®, and Miralax® failed to offer her symptomatic relief. Intestinal lavage with a balanced electrolyte solution did not produce significant output nor did it produce clinical improvement. Several large-volume hyperosmolar enemas were administered without clinical or radiographic improvement.
Repeat abdominal radiograph once again showed a large amount of fecal material throughout the entire colon without signs of mechanical obstruction (Fig. 1A). It was decided to try intravenous neostigmine. After informed consent was obtained, the patient was transferred to the pediatric intensive care unit for continuous cardiorespiratory monitoring. Atropine was available at the bedside. Two milligrams of neostigmine (1:1000) were diluted in 10 ml of 5% dextrose and infused intravenously over 8 minutes. Five minutes into the infusion, the patient experienced lacrimation, twitching of her eyes, mild facial flushing, and abdominal cramping. Approximately 12 minutes after the infusion was completed, the patient passed two very large bowel movements. She continued to experience abdominal cramping for approximately 45 minutes; however, it diminished significantly following passage of stool. Her heart rate and blood pressure did not change significantly during the infusion. An abdominal radiograph performed several hours following the neostigmine infusion demonstrated substantial improvement (Fig. 1B). During the next 24 hours, the patient experienced a significant decrease in abdominal distention and discomfort. She tolerated her overnight tube feedings without nausea, bloating, or vomiting. The following day, an additional 2 mg of neostigmine were administered intravenously over five minutes. The patient experienced lacrimation and tightness in her throat as well as difficulty swallowing for 5 minutes after the infusion was completed. She passed a large amount of soft stool and all of her complaints resolved. She reported feeling much better after the second infusion and she was discharged home two days later.
In the next three months, the patient was admitted to the hospital two more times for exacerbations of her lung disease. During each of those hospitalizations she complained of constipation, abdominal pain, abdominal bloating, and feeding intolerance and she was treated with 2 mg of neostigmine administered by vein over five minutes. On both occasions, she produced two very large bowel movements and experienced marked symptomatic improvement. With each infusion, she experienced transient nausea, lacrimation, and blurred vision but no other complications.
DISCUSSION
In 1941, Rasor and Stevenson described acute intestinal obstruction in children with cystic fibrosis beyond the neonatal period (11). In the early 1960's Jenson used the term meconium ileus equivalent to emphasize the similarities between this condition and the intestinal obstruction of some newborn infants with cystic fibrosis (12). Recently, the term meconium ileus equivalent has largely been replaced with the term distal intestinal obstruction syndrome, or DIOS.
The symptoms associated with distal intestinal obstruction syndrome arise from partial or complete intestinal obstruction. Affected individuals frequently experience constipation, abdominal pain, anorexia, and early satiety. On physical examination, there may be a palpable cecal mass (6). Chronic or recurrent abdominal pain can precede the signs and symptoms of intestinal obstruction by weeks or months. Recurrent vomiting due to the partial intestinal obstruction may be the presenting complaint (1,6).
Distal intestinal obstruction syndrome is unique to cystic fibrosis and does not occur with other forms of pancreatic insufficiency. The pathophysiology of the disorder is unclear. It has been hypothesized that distal intestinal obstruction syndrome results from a combination of exocrine pancreatic insufficiency, abnormal intestinal mucous, and slow transit time through the small intestine (1,8,13) resulting in semisolid or solid fecal material in the terminal ileum instead of the usual liquid content (1,13). The mass of abnormal fecal material may cause partial or total intestinal obstruction. The mass may be confined to the terminal ileum or may extend into the cecum and ascending colon. On occasion, the mass may adhere so tightly to the inner surface of the bowel wall that removal can only be accomplished by stripping the superficial epithelium (14).
The prevalence of distal intestinal obstruction syndrome in patients with cystic fibrosis was initially reported to be between 5 and 15%, but more recent reports suggest the prevalence may be much higher, ranging from 30 and 73% (2). Up to 40% of patients with cystic fibrosis experience chronic or recurrent constipation (13,15) and 42% of patients with distal intestinal obstruction syndrome have a history of constipation (16). Distal intestinal obstruction syndrome is uncommon in children under five years of age and occurs more commonly during adolescence and young adulthood (1,2,6,15). Some authors have hypothesized that the increased frequency of this disorder in older patients is due to the relative decrease in the amount of supplemental pancreatic enzymes in older and larger patients (1). However, no clear association between the incidence of distal intestinal obstruction syndrome and the dose of pancreatic enzymes has been found (13), nor is there any association between distal intestinal obstruction syndrome and the degree of steatorrhea (8).
Many therapeutic strategies have been used to treat distal intestinal obstruction syndrome. Oral administration of mineral oil, N-acetylcysteine, or Gastrograffin® have be used to break up or lubricate the abnormal intestinal contents (3-7). More recently, a number of authors have reported that intestinal lavage with a balanced electrolyte solution is an effective treatment (3,4,6). Enemas containing a variety of substances have been used, but are less likely to be helpful if the site of the obstruction is the terminal ileum (2). N-acetylcysteine has been administered as an enema, sometimes in combination with oral or nasogastric N-acetylcysteine. Resolution of symptoms has also been described after single or repeated oral doses and/or enemas of the radiocontrast material Gastrograffin® which is quite hyperosmolar (2150 mOsm/L). In rare cases, surgery may be required (2,8,9).
Recurrences of distal intestinal obstruction syndrome are common and some patients experience multiple recurrences (4,8). Several strategies have been proposed to lessen the frequency of recurrences (6,8,17). Although no studies have examined the role of prokinetic agents in treating acute episodes of distal intestinal obstruction syndrome, one prospective trial has suggested that chronic cisapride therapy lessens the recurrence risk (10).
Acute colonic pseudo-obstruction syndrome, sometimes called Olgivie's syndrome, is a severe form of colonic ileus characterized by colonic dilatation in the absence of any associated mechanical obstruction. While the etiology and pathophysiology of acute colonic pseudo-obstruction syndrome and distal intestinal obstruction syndrome are quite different, there are a number of clinical similarities between these two disorders.
Acute colonic pseudo-obstruction is defined as colonic distention with a cecal diameter of at least 10 cm on plain abdominal radiograph without any evidence of mechanical obstruction. This disorder is most commonly seen in elderly patients, often following trauma or abdominal, pelvic, or orthopedic surgical procedures (19). While the pathogenesis of acute colonic pseudo-obstruction remains unclear, a number of authors have proposed that the disorder results from an imbalance in the autonomic regulation of colonic motor activity. Normally, the parasympathetic nervous system increases colonic motility while the sympathetic nervous system decreases colonic motility. Acute colonic pseudo-obstruction syndrome may result from either excessive suppression of the parasympathetic system, excessive stimulation of the sympathetic system, or both (18-22). In his initial description of this disorder, Olgivie described two patients who developed symptoms following malignant infiltration of the celiac plexus and speculated that colonic pseudo-obstruction might be caused by an alteration of sympathetic tone in the colon (23). More recently, there have been a number of reports of acute colonic pseudo-obstruction syndrome precipitated by the use of anticholinergic agents such as amitriptyline, doxepin, and clonidine (22).
Several pharmacological agents have been used to treat acute colonic pseudo-obstruction syndrome including erythromycin, cisapride, and metoclopramide. Results have been variable (18). More recently, a number of authors have suggested that neostigmine might be an effective means of treating this disorder. Neostigmine is a potent parasympathomimetic agent. It is an acetylcholinesterase inhibitor that increases synaptic levels of acetylcholine and enhances colonic motility (20). When administered intravenously, neostigmine has a circulating half-life of approximately 80 minutes. It is hydrolyzed by plasma cholinesterase and metabolized in the liver (24). Side effects associated with neostigmine infusion include salivation, nausea, vomiting, abdominal pain, and bradycardia, all of which can be readily reversed with atropine (18,21,22). Neostigmine may also increase pulmonary secretions and bronchial reactivity, potentially exacerbating bronchospasm (21). In three uncontrolled studies, 80% of patients with acute colonic pseudo-obstruction experienced clinical improvement after a single intravenous infusion of neostigmine (18). In a recent randomized placebo-controlled trial, 91% of patients treated with a single dose of intravenous neostigmine experienced an immediate clinical response compared with none of the patients in the placebo-treated group (21). A recent case report suggested that neostigmine might be effective in treating exacerbations of chronic intestinal pseudo-obstruction syndrome (22). No serious complications or adverse events have been reported in any of these case reports.
Encouraged by these reports, we elected to treat our patient's refractory and persistent distal intestinal obstruction syndrome with intravenous neostigmine. She experienced an immediate and dramatic clinical and radiologic response. Although she did not experience any serious side effects from neostigmine, we recognize that a potent parasympathomimetic agent is not without risk in a patient with significant pulmonary disease. Until additional observations are made regarding the safety and efficacy of neostigmine in refractory or persistent distal intestinal obstruction syndrome, its use should be reserved for those cases that have proven refractory to more traditional and proven modes of therapy.
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